tbuckley/cabot-search huggingface dataset:
First-line (1L) nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients (pts) with metastatic non–small cell lung cancer (NSCLC): 3-year update from CheckMate 9LA.
Authors: Luis G. Paz-Ares, Tudor-Eliade Ciuleanu, Manuel Cobo-Dols, Jaafar Bennouna, Ying Cheng, Hideaki Mizutani, Alejo Lingua, Felipe Reyes, Niels Reinmuth, Juliana Janoski De Menezes, Jacek Jassem, Svetlana Protsenko, Kynan Feeney, Emmanuel De La Mora Jimenez, Shun Lu, Tom John, David Paul Carbone, Xiaoqing Zhang, Nan Hu, Martin Reck
Journal: Journal of Clinical Oncology (2022)

LBA9026 Background: In CheckMate 9LA (NCT03215706), 1L NIVO + IPI combined with 2 cycles of chemo was shown to provide survival benefit vs chemo alone in pts with metastatic NSCLC. Here, we report updated efficacy and safety with a 3-year minimum follow-up, as well as exploratory biomarker analyses from this study. Methods: Adults with stage IV or recurrent NSCLC, no known sensitizing EGFR/ ALK alterations, and ECOG performance status ≤ 1 were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + 2 cycles of chemo (n = 361) or 4 cycles of chemo alone (n = 358). Pts were stratified by tumor PD-L1 expression, sex, and histology. Pts with non-squamous (NSQ) NSCLC in the chemo-alone arm could receive pemetrexed maintenance. Assessments included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). For all pts with NSQ NSCLC and with tissue evaluable for mutational analysis (n = 313), the FoundationOne CDxTM assay was used to identify mutant (mut) or wild type (wt) KRAS and STK11 genes. Exploratory assessments included evaluation of OS and PFS with NIVO + IPI + chemo vs chemo by mutation status and safety. Results: At a minimum follow-up of 36.1 mo (database lock: Feb 15, 2022), pts continued to derive long-term, durable OS benefit with NIVO + IPI + chemo vs chemo (HR, 0.74 [95% CI, 0.62–0.87]); 3-y OS rates were 27% vs 19%. Clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across most subgroups, including by PD-L1 expression level (Table) or histology. In an exploratory analysis in pts evaluable for mutations including KRAS and STK11, OS appeared to be improved with NIVO + IPI + chemo vs chemo (median OS, 16.3 vs 13.1 mo). Similar trends of prolonged OS with NIVO + IPI + chemo vs chemo were also seen in pts with or without KRAS mutation (median OS, mut: 19.2 vs 13.5 mo; wt: 15.6 vs 12.7 mo) or STK11 mutation (mut: 13.8 vs 10.7 mo; wt: 17.8 vs 13.9 mo), respectively. Additional efficacy outcomes will be presented. No new safety signals were identified with extended follow-up. Conclusions: With a 3-year minimum follow-up, 1L NIVO + IPI + chemo demonstrated long-term, durable efficacy benefit vs chemo in pts with metastatic NSCLC. Survival benefit of NIVO + IPI + chemo vs chemo was observed regardless of KRAS and STK11 mutation status. Clinical trial information: NCT03215706. [Table: see text]
ATHENA–MONO (GOG-3020/ENGOT-ov45): A randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as maintenance treatment following response to first-line platinum-based chemotherapy in ovarian cancer.
Authors: Bradley J. Monk, Christine Parkinson, Myong Cheol Lim, David M. O'Malley, Ana Oaknin, Michelle K. Wilson, Robert L. Coleman, Domenica Lorusso, Amit M. Oza, Sharad A. Ghamande, Athina Christopoulou, Emily Prendergast, Fuat Demirkiran, Ramey D. Littell, Anita M. Chudecka-Glaz, Mark Aloysuis Morgan, Sandra M. Goble, Stephanie Hume, Keiichi Fujiwara, Rebecca Kristeleit
Journal: Journal of Clinical Oncology (2022)

LBA5500 Background: While PARP inhibitors have shown efficacy as first-line (1L) maintenance treatment for patients (pts) with ovarian cancer (OC), questions remain about the pt population that may benefit from their use. ATHENA (NCT03522246) was designed to test if rucaparib may be effective as 1L maintenance treatment in a broad pt population, including those without BRCA mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. Here we report results from the ATHENA–MONO comparison of rucaparib vs placebo. Methods: Pts with stage III–IV high-grade OC who had completed cytoreductive surgery (R0 permitted) and 4–8 cycles of 1L platinum-doublet (bevacizumab allowed with chemotherapy) with a response were randomized 4:1 to oral rucaparib 600 mg BID or placebo. Pts were stratified by HRD status (as determined by FoundationOne CDx), residual disease status after chemotherapy, and timing of surgery. The primary endpoint of investigator-assessed PFS per RECIST was assessed in a step-down procedure first in the HRD population (BRCA mutant or BRCA wild-type/loss of heterozygosity [LOH] high carcinoma) and then in the intent-to-treat (ITT) population. Blinded independent central review (BICR)–assessed PFS was a stand-alone, secondary endpoint. PFS in BRCA mutant and HRD-negative pts (BRCA wild-type/LOH low) were exploratory endpoints. Results: As of Mar 23, 2022 (visit cutoff), 427 and 111 pts were randomized to rucaparib monotherapy or placebo (median time on treatment, 14.7 and 9.9 mo). PFS data are shown in the Table. Most common grade ≥3 TEAEs were anemia (rucaparib, 28.7% vs placebo, 0%), neutropenia (14.6% vs 0.9%), and ALT/AST increased (10.6% vs 0.9%). Rucaparib dose reduction, interruption, and discontinuation due to TEAEs occurred in 49.4%, 60.7%, and 11.8% of pts. Conclusions: Rucaparib monotherapy is effective as 1L maintenance with significant benefit vs placebo observed in the ITT and HRD populations, as well as the non-nested subgroup of pts without known HRD. Clinical trial information: NCT03522246. [Table: see text]
Randomized phase III trial on trabectedin (ET-743) single agent versus clinician’s choice chemotherapy in recurrent ovarian, primary peritoneal, or fallopian tube cancers of BRCA-mutated or BRCAness phenotype patients (MITO23).
Authors: Giovanni Scambia, Francesco Raspagliesi, Giorgio Valabrega, Nicoletta Colombo, Carmen Pisano, Chiara Cassani, Germana Tognon, Stefano Tamberi, Giorgia Mangili, Serafina Mammoliti, Ugo De Giorgi, Filippo Greco, Anna Maria Mosconi, Enrico Breda, Grazia Artioli, Claudia Andreetta, Claudia Casanova, Rita Ceccherini, Antonio Frassoldati, Domenica Lorusso
Journal: Journal of Clinical Oncology (2022)

LBA5504 Background: Trabectedin demonstrated antitumor activity when administered as single agent in relapsed platinum sensitive ovarian cancer (OC), with an overall response rate (ORR) ranging from 26 to 43% and a median PFS of 5 months. In addition, trabectedin showed 39.4% RR, 4.5 months median progression free survival (PFS) and 18 months median overall survival (OS) in a single arm phase 2 trial in recurrent BRCA mutated and/or the BRCAness phenotype OC patients. Methods: In this open-label, phase III, randomized trial, we assigned recurrent OC patients harboring BRCA 1/2 mutations or with BRCAness phenotype (defined as patients who had received and responded to at least 2 previous platinum-based treatments) to receive trabectedin 1.3 mg/mq q 21d or physician’s choice chemotherapy (among carboplatin, gemcitabine, weekly paclitaxel, pegylated liposomal doxorubicine or topotecan). The primary endpoint was OS. Secondary endpoints were PFS, ORR and Duration of Response (DoR). The sample size was calculated based on the assumption that trabectedin would increase median OS from 10 to 15 months (two-sided log-rank test at the error alfa= 0.05 and a power of 80%). Medians and lifetables were computed using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards model was used to assess the effect of treatment. Results: Two hundred and forty-four patients were randomized and analyzed based on the intent-to-treat principle. At a median follow up of 40 months, the median PFS was 4.4 and 4.9 months (HR= 1.03 p=0.848) and median OS was 17.9 and 15.8 months (HR=1.15 p=0.304), in the control and experimental arm, respectively. ORR was 20.2% in the group of patients receiving standard chemotherapies and 15.4% in the group of patients treated with trabectedin. No superior effect was reported for Trabectedin in the pre-specified sub-group analysis according to BRCA mutational status, type of chemotherapy and platinum-free interval. No new signal of toxicity were reported for all the chemotherapies employed. Conclusions: Trabectedin as single agent does not improve survival outcomes when compared to standard chemotherapy in BRCA mut and BRCAness phenotype OC patients. Clinical trial information: NCT02993705.
Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases, first results from a phase III randomized controlled multicenter trial (the SCANDIUM trial).
Authors: Roger Olofsson Bagge, Axel Nelson, Amir Shafazand, Charlotta All-Ericsson, Christian Cahlin, Nils Elander, Hildur Helgadottir, Jens Folke Kiilgaard, Sara Kinhult, Ingrid Ljuslinder, Magnus Rizell, Malin Sternby Eilard, Gustav J. Ullenhag, Jonas A Nilsson, Lars Ny, Per Lindner
Journal: Journal of Clinical Oncology (2022)

LBA9509 Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of the patients, with the liver being the most common site. The median survival for patients with liver metastases is about 6-12 months, and there are only few systemic treatment options available that moderately prolong survival. A previous trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival, compared with a historical control group consisting of the longest surviving patients in Sweden during the same time period (26 vs. 12 months). Methods: In this multicenter randomized, controlled, phase III trial, patients with previously untreated isolated liver metastasis from uveal melanoma were randomized between 2013 and 2021 to receive IHP or best alternative care (control group). The primary end point is overall survival at 24 months, but here we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS) and toxicity. Results: A total of 93 patients were randomized, with three patients in each group being excluded due to either withdrawal of consent or inappropriate enrollment, and a total of 87 patients were assigned to either IHP group (43 patients) or control group (44 patients). In the IHP group, 41 (89%) patients were treated per protocol, and in the control group, 49% of the patients were treated with chemotherapy, 39% with immunotherapy and 9% with localized treatment interventions. In an intention-to-treat analysis, the overall response rate (ORR) in the IHP group was 40% (17/43) compared to 4.5% (2/44) in the control group (p&lt;0.0001). The median hPFS in the IHP group was 9.1 months (95% CI, 5.6 to 13.4 months), compared to 3.3 months (95% CI, 2.9 to 4.0 months) in the control group (p&lt;0.0001). The median PFS in the IHP group was 7.4 months (95% CI, 5.2 to 11.6 months), compared to 3.3 months (95% CI, 2.9 to 3.7 months) in the control group (p&lt;0.0001). There were 14 treatment-related serious adverse events in the IHP group, where vascular complication and infections were the most common side effects, compared to 13 in the control group where immunotherapy related side effects were most common. There was one treatment related death in the IHP group. Conclusions: Treatment with IHP resulted in superior ORR, hPFS and PFS compared to best alternative care among previously untreated patients with isolated uveal melanoma liver metastasis. Clinical trial information: NCT01785316.
CALYPSO: A three-arm randomized phase II study of durvalumab alone or with savolitinib or tremelimumab in previously treated advanced clear cell renal cancer.
Authors: Thomas Powles, Maria Jose Mendez-Vidal, Alejo Rodriguez-Vida, Begoña Pérez-Valderrama, Emilio Esteban, Fiona Thistlethwaite, Poulam M. Patel, Urbano Anido Herranz, Gopalakrishnan Srinivasan, Abdel Hamid, James Larkin, Christy Ralph, Stefan N. Symeonides, Javier Puente, Ryan Hartmaier, Aleksandra Markovets, Aaron Prendergast, Kelly Mousa, Cristina Suarez
Journal: Journal of Clinical Oncology (2022)

LBA4503 Background: New drug combinations are required in advanced clear cell renal cancer (RCC). These potentially include MET inhibition with savolitinib (S) or CTLA-4 inhibition with tremelimumab (T). In this study these agents were given alone or in combination with the PD-L1 inhibitor durvalumab (D). Methods: A multinational open-label randomised phase II study assigning patients to one of D, S, DT or DS was performed. Patients with RCC, who had previously received VEGF targeted therapy but not immune checkpoint inhibitors or MET inhibitors were included. Confirmed response rate (cRR) was the primary endpoint. A response rate of at least 50% was required for further exploration. The S arm was closed early due to a lack of efficacy. DNA alterations were measured using Foundation One and PD-L1 analysis was performed with SP263. This abstract details the pre-planned 12-month interim analyses after the cohort completed randomisation. Results: Between 2017 and 2021, 139 patients were randomised (D N=39, S N=22, DT N=39, DS N=39). The median age was 62 years (range: 28 – 85). cRRs for the 4 arms were D=10%, S=5%, DT=28%, DS=13%, which did not meet the primary objective. cRRs in the MET-driven patients (N=17) were D=0% (0/7), S=0% (0/2), DT=50% (1/2), DS=17% (1/6). cRRs in PD-L1+ves for DT and D were 14% (1/7) and 33% (2/6) respectively. 12-month progression-free survival (PFS) rates were D=26% (80% confidence interval [CI]: 17% - 36%), S=21% (80% CI: 10% - 35%), DT=33% (80% CI: 24% - 43%), DS=17% (80% CI: 10% - 26%). Median overall survival for D=26.1 (80% CI: 16.2 – 32.0) months, S=23.1 (80% CI: 20.6 – 29.7) months, DT=21.9 (80% CI: 16.3 – 31.5) months, DS=16.1 (80% CI: 10.3 – 18.8) months. There was 1 treatment related death in the DT arm. Of the 136 patients who received treatment, grade 3 or more treatment related adverse events occurred in D=10% (4/39), S=26% (5/19), DT=23% (9/39), DS=23% (9/39). Conclusions: This randomised phase II study did not demonstrate significant efficacy for S alone or in combination with D in RCC. The addition of T to D did not demonstrate clearly superior efficacy to D in this setting. Clinical trial information: NCT02819596.
Understanding the mechanism behind preoperative exercise therapy in patients with gastrointestinal cancers: A prospective, randomized clinical trial.
Authors: Ahmad Hamad, Hongji Zhang, Hai Huang, Aslam Ejaz, Allan Tsung
Journal: Journal of Clinical Oncology (2022)

LBA4087 Background: Upwards of 50% of patients who undergo gastrointestinal (GI) cancer surgery will not receive any chemotherapy due to the failure to heal from the surgery or its associated complications. Pre-operative exercise therapy (PEx) aims to optimize the medical and physical state of high-risk patients prior to undergoing surgery. Our group has shown PEx to be protective against the inflammatory injury caused by surgical stress in mice through a metabolic reprogramming towards an anti-inflammatory profile. However, there is a gap in knowledge regarding the utility of PEx among GI cancer patients undergoing surgery and how PEx impacts surgical outcomes. This study seeks to evaluate the mechanism behind PEx among patients undergoing major abdominal surgery for GI cancer through a randomized controlled trial. Methods: Eligible patients diagnosed with GI cancers with planned abdominal surgery were randomized to receive PEx or no PEx between September 2020 and March 2022. PEx patients were evaluated by a physical therapist (PT) and prescribed a personalized training regimen based on objective assessments. Patient blood was drawn on the day of enrollment, day of surgery, then at 2 weeks and at 3 months following surgery. The primary endpoint is to investigate the mechanism behind the modulation of the inflammatory response of PEx among patients undergoing GI cancer surgery. Results: During an 18-month period, 30 patients were randomized to PEx and 35 randomized to non-PEx. Both cohorts were similar in age, gender, and comorbidity burden. Using patient serum samples, the secretome revealed a transcriptomic shift towards an anti-inflammatory and anti-tumorigenic phenotype in post-PEx patient blood samples when compared to pre-PEx and non-PEX patients. The secretome heatmap demonstrates significant changes post-PEX when compared to pre-PEx and non-PEX. Specifically, there was an upregulation of Esterase D protein (ESTD), Secreted Ly-6/uPAR-related protein 1 (SLUR1), tissue inhibitor of metalloproteinase (TIMP), and Phosphoinositide-3-kinase interacting protein 1 (P3IP1) which are associated with an anti-inflammatory and anti-tumorigenic phenotype. Moreover, there was a downregulation of pro-tumorigenic protein pathways including ankyrin 1 protein (ANK1), KIT protein, and Prolyl isomerase protein (PIN1). Additionally, gene ontology analysis used to evaluate differentially expressed proteins, revealed that proteins associated with lymphocyte mediated immunity were downregulated after PEx. Conclusion: Preoperative exercise may mitigate the pro-inflammatory and pro-tumorigenic state of cancer by the upregulation and downregulation of specific cellular pathways. Data obtained from this study can be used to create a new class of therapeutics, exercise mimetics. Clinical trial information: NCT04602026.
Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer.
Authors: Andrea Cercek, Melissa Amy Lumish, Jenna Cohen Sinopoli, Jill A. Weiss, Jinru Shia, Zsofia Kinga Stadler, Rona Yaeger, Jesse Joshua Smith, Leonard B. Saltz, Imane H. El Dika, Christopher H. Crane, Paul Bernard Romesser, Kirshna Iyer, Philip Paty, Julio Garcia-Aguilar, Mithat Gonen, Marc J Gollub, Martin R. Weiser, Kurt A. Schalper, Luis A. Diaz
Journal: Journal of Clinical Oncology (2022)

LBA5 Background: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is mismatch repair deficient. Since mismatch repair deficient colorectal cancer is responsive to PD-1 blockade in the metastatic setting, we hypothesized that locally advanced mismatch repair deficient rectal cancer is sensitive to checkpoint blockade and may alter the requirements for chemoradiotherapy and surgery. Methods: We conducted a prospective phase II study in which single agent dostarlimab, an anti PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair deficient stage II and III rectal adenocarcinoma, to be followed by standard chemoradiation and surgery. Patients who achieved a clinical complete response were eligible for omission of chemoradiation and surgery. Results: Twelve patients initiated treatment and have at least 6 months of follow up. All 12 (100%, 95% CI:74%-100%) achieved a clinical complete response with no evidence of tumor on MRI, FDG-PET, endoscopic visualization, digital rectal exam, or biopsy, which satisfied the study’s co-primary endpoint. To date, no patients have required chemoradiation or surgery, and no cases of progression or recurrence have been noted during follow up (range 6-25 months). No serious adverse events &gt; grade 3 were observed. Conclusions: Mismatch repair deficient locally advanced rectal cancer is exceptionally sensitive to single agent PD-1 blockade. Longer follow up is needed to assess response duration. Clinical trial information: NCT04165772.
Distant metastasis-free survival with pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: The phase 3 KEYNOTE-716 study.
Authors: Georgina V. Long, Jason J. Luke, Muhammad Khattak, Luis de la Cruz Merino, Michele Del Vecchio, Piotr Rutkowski, Francesco Spagnolo, Jacek Mackiewicz, Vanna Chiarion-Sileni, John M. Kirkwood, Caroline Robert, Jean-Jacques Grob, Federica de Galitiis, Dirk Schadendorf, Matteo S. Carlino, Larry Wu, Mizuho Fukunaga-Kalabis, Clemens Krepler, Alexander M. Eggermont, Paolo Antonio Ascierto
Journal: Journal of Clinical Oncology (2022)

LBA9500 Background: In previous analyses of the phase 3, double-blind KEYNOTE-716 study, adjuvant pembrolizumab (pembro) significantly improved recurrence-free survival compared with placebo in patients (pts) with resected AJCC-8 stage IIB or IIC melanoma. We present new data from the analysis of distant metastasis-free survival (DMFS), and recurrence-free survival (RFS) with longer follow up. Methods: A total of 976 pts aged ≥12 years with complete resection of cutaneous stage IIB or IIC melanoma and negative sentinel lymph node biopsy were randomized 1:1 to pembro 200 mg (2 mg/kg for pediatric pts) or placebo Q3W for 17 cycles (approximately 1 year) in Part 1 of the study. Randomization was stratified by T category 3b, 4a, 4b (adults) with a separate stratum for pediatric pts. Treatment continued until disease recurrence or unacceptable toxicity. Pts who received placebo in Part 1, or who did not experience disease progression within 6 months of completing Part 1 were eligible for additional cycles of pembro Q3W at recurrence (Part 2). The primary endpoint was RFS per investigator. DMFS by investigator is a secondary endpoint. The data cut-off date for this interim analysis was Jan 4th, 2022. Results: At median follow-up of 26.9 mo (range, 4.6-39.2), adjuvant pembro significantly improved DMFS (HR 0.64, 95% CI, 0.47-0.88; P=0.0029; median not reached [NR] for both) vs placebo. The 24-mo DMFS rate was 88.1% vs 82.2%. There was consistent reduction in the risk of recurrence with pembro vs placebo (HR 0.64, 95% CI, 0.50-0.84) with further follow-up. The 24-mo RFS rate was 81.2% vs 72.8%. Grade ≥ 3 any-cause AEs occurred in 137 (28.4%) vs 97 (20.0%) pts in the pembro vs placebo arms. Grade ≥ 3 drug-related AEs occurred in 83 (17.2%) vs 24 (4.9%) pts. One pt in the pembro arm and 5 pts in the placebo arm died due to an any-cause AE. No deaths were drug-related. Immune-mediated AEs occurred in 182 (37.7%) vs 45 (9.3%) pts, most commonly hypothyroidism (17.2% vs 3.7%). Conclusions: Adjuvant pembrolizumab vs placebo for resected stage IIB and IIC melanoma significantly improved DMFS, with continued reduction in the risk of recurrence, and a favorable benefit-risk profile. Clinical trial information: NCT03553836.
IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer
Authors: Yunfei He, Wenqian Luo, Yingjie Liu, Yuan Wang, Chengxin Ma, Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Xianzhe Lv, Yu-Shui Ma, Haitang Yang, Ke Xu, Xue Zhang, Yansen Xiao, Peiyuan Zhang, Yajun Liang, Da Fu, Feng Yao, Guohong Hu
Journal: Journal of Clinical Investigation (2022)

Bone is a common site of metastasis in lung cancer, but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL receptor 20 subunit β (IL-20RB) mediated a direct tumoral response to osteoclasts. Tumoral expression of IL-20RB was associated with bone metastasis of lung cancer, and functionally, IL-20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL-20RB ligand IL-19, and IL-19 stimulated IL-20RB-expressing tumor cells to activate downstream JAK1/STAT3 signaling, leading to enhanced proliferation of tumor cells in bone. Importantly, blocking IL-20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct protumor role of osteoclastic niche in bone metastasis and supported IL-20RB-targeting approaches for metastasis treatment.